Chimeric Antigen Receptors (CAR) are fusion proteins that combine an extracellular antigen recognition domain with an intracellular co-stimulatory signaling domain. Natural Killer (NK) cells are modified genetically to allow insertion of a CAR. CAR-NK cell therapy has demonstrated initial clinical relevance without the limitations of CAR-T, such as Cytokine Release Syndrome, neurotoxicity or Graft vs Host Disease (GVHD). In addition, CAR-NKs are naturally allogeneic, available off-the-shelf and may be able to be administered on an outpatient basis. Recent innovative developments with the induced pluripotent stem cell (iPSC)-derived CAR-NKs, an innovative technology, allow large quantities of homogeneous genetically modified CAR NK cells to be produced from a gene-edited iPSC master cell bank, and thus hold promise to expand access to cell therapy for many patients.
This week, Cytovia Therapeutics, an emerging biopharmaceutical company focusing on Natural Killer cells in cancer, announced that it has signed a licensing agreement with the National Cancer Institute (NCI), part of the National Institutes of Health, to apply its gene-edited iPSC-derived NK cell technology to develop GPC3 CAR NK cell therapeutics. Dr Mitchell Ho, PhD, Director of the Antibody Engineering Program and Deputy Chief of the Laboratory of Molecular Biology at the NCI Center for Cancer Research has developed novel antibodies and chimeric antigen receptors (CAR) binding to glypican-3 (GPC3) on liver cancer cells. Dr. Ho has published data on the humanized GPC3 antibody in scientific reports (nature research) in 2016 as well as on the GPC3 CAR in Gastroenterology in 2020.
GPC3 is an oncofetal antigen involved in Wnt-dependent cell proliferation. It is highly expressed in Hepatocellular Carcinoma tumor cells as well as multiple other solid tumors, including ovarian cancer and lung cancer, but not expressed in adult normal tissues.
Cytovia has also signed a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute. Under the CRADA, Cytovia will collaborate with Dr. Ho’s laboratory to develop and evaluate gene-edited iPSC-derived GPC3 CAR NK cells. Cytovia expects to file an initial new drug application (IND) for its GPC3 CAR NK cells in the first half of 2022.
Dr. Daniel Teper, Chairman and CEO of Cytovia Therapeutics commented: “GPC3 is an exciting new validated target for Hepatocellular Carcinoma, an area of major unmet medical need, as well as other solid tumors. We look forward to collaborating with Dr. Ho, a pioneer in GPC3 research, to develop a novel gene-edited, iPSC-derived GPC3 CAR NK that will advance toward a cure for liver cancer.”
Dr. Ho added: “Natural Killer cells play a major role in the immuno-surveillance of liver cancer. GPC3 is expressed in more than 70% of Hepatocellular Carcinoma cells but not on healthy cells. We look forward to investigating whether GPC3 CAR-NK therapy could provide a new safe and effective off-the-shelf option for patients with liver cancer.”
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of death worldwide, with 800,000 new cases diagnosed globally every year. The incidence in Asia is amongst the highest in the world (75%) with 400,000 in China alone. In the US, it is estimated to reach upwards of 30,000 by the end of 2020 and continues to be on the rise. Despite advances in immunotherapy, with current treatment options including multi-kinase inhibitors (TKI) and checkpoint inhibitors, life expectancy for patients diagnosed with HCC remains very low. The disease is often diagnosed at an advanced stage, with a median survival of approximately 6 to 20 months following diagnosis, and a 5-year survival rate below 10% in the US. Fortunately, new options including cell therapy and bispecific antibodies offer promise towards a cure for liver cancer.
Glypican-3 (GPC3) is a cell-surface heparan sulfate proteoglycan expressed in the liver and the kidney of fetuses but is hardly expressed in adults, except in the placenta. However, it is highly expressed in HCC, ovarian clear cell carcinoma, squamous cell carcinoma of the lung, melanoma, hepatoblastoma, nephroblastoma (Wilms tumor), yolk sac tumor, and some pediatric cancers. GPC3 promotes Wnt-dependent cell proliferation and has been strongly suggested that it is related to the malignant transformation. Therefore, GPC3 is a promising target for cancer immunotherapy and can serve as a biomarker for predicting tumor recurrence and treatment efficacy.
Cytovia Therapeutics Inc is an emerging biotechnology company that aims to accelerate patient access to transformational immunotherapies, addressing several of the most challenging unmet medical needs in cancer. Cytovia focuses on Natural Killer (NK) cell biology and is leveraging multiple advanced patented technologies, including an induced pluripotent stem cell (iPSC) platform for CAR (Chimeric Antigen Receptors) NK cell therapy, next-generation precision gene-editing to enhance targeting of NK cells, and NK engager multi-functional antibodies. Our initial product portfolio focuses on both hematological malignancies such as multiple myeloma and solid tumors including hepatocellular carcinoma and glioblastoma. The company partners with the University of California San Francisco (UCSF), the New York Stem Cell Foundation (NYSCF), the Hebrew University of Jerusalem, INSERM, and CytoImmune Therapeutics.